@article{7817a7451fdf41a0812610caabe1bb24,
title = "Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy",
abstract = "Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T-cell, natural killer, macrophage and dendritic cell populations enriched in BRCA2-deficient tumors. Taken together, our findings reveal the divergent effects of BRCA1 and BRCA2 deficiency on ICB outcome and have important implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.",
author = "Samstein, {Robert M.} and Chirag Krishna and Xiaoxiao Ma and Xin Pei and Lee, {Ken Wing} and Vladimir Makarov and Fengshen Kuo and Jonathan Chung and Srivastava, {Raghvendra M.} and Purohit, {Tanaya A.} and Hoen, {Douglas R.} and Rajarsi Mandal and Jeremy Setton and Wei Wu and Rachna Shah and Besnik Qeriqi and Qing Chang and Sviatoslav Kendall and Lior Braunstein and Britta Weigelt and {Blecua Carrillo Albornoz}, Pedro and Morris, {Luc G.T.} and Mandelker, {Diana L.} and Reis-Filho, {Jorge S.} and {de Stanchina}, Elisa and Powell, {Simon N.} and Chan, {Timothy A.} and Nadeem Riaz",
note = "Funding Information: We thank the members of the Chan laboratory, the Immunogenomics and Precision Oncology Platform, the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology, the Medical Genetics Service at MSKCC and the Department of Pathology for helpful discussions. We also thank MSKCC core laboratories including the Anti-Tumor Assessment, Molecular Cytology, Cytogenetics and Flow Cytometry cores. J.S.R.-F. and S.N.P. are funded in part by the Breast Cancer Research Foundation. This study was funded in part through the National Institutes of Health (NIH)/National Cancer Institute Cancer Center Support Grant P30 CA008748. We acknowledge funding sources, including Pershing Square Sohn Cancer Research grant (T.A.C.), the PaineWebber Chair (T.A.C.), Stand Up 2 Cancer (T.A.C.), NIH R01 CA205426, NIH R35 CA232097 (T.A.C.), the STARR Cancer Consortium (T.A.C.), AACR Translational Immunology (R.M.S.), NIH Director{\textquoteright}s Early Independence Award, DP5-OD028171 (R.M.S.), Burroughs Wellcome Fund Career Award for Medical Scientists (R.M.S.), Precision Immunotherapy Kidney Cancer Fund (T.A.C., R.J.M.), Frederick Adler Fund (L.G.T.M.) and NIH U54 OD020355 (E.D.S.). Funding Information: T.A.C. is a co-founder of Gritstone Oncology and holds equity, holds equity in An2H and acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H and Eisai. L.G.T.M. receives research funding from AstraZeneca. T.A.C. has served as an advisor for Bristol-Myers Squibb, Illumina, Eisai and An2H. MSK has licensed the use of TMB for the identification of patients who benefit from immune checkpoint therapy to PGDx. MSK, R.M.S., L.G.T.M. and T.A.C. receive royalties as part of this licensing agreement. J.S.R.-F. reports personal/ consultancy fees from Goldman Sachs and membership of the advisory boards of VolitionRx, Page.AI, Invicro, Roche, Genentech and Ventana, outside the submitted work. N.R. has received research funding from BMS, Pfizer and REPARE Therapeutics and has served as an ad hoc consultant to Illumina, REPARE Therapeutics and Mirati Therapeutics. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature.",
year = "2020",
month = dec,
doi = "10.1038/s43018-020-00139-8",
language = "English (US)",
volume = "1",
pages = "1188--1203",
journal = "Nature Cancer",
issn = "2662-1347",
publisher = "Nature Research",
number = "12",
}